The interplay between cytokine genes and microRNAs in anemia of inflammation among hemodialysis patients

Abstract

Abstract Anemia of inflammation (AI) represents the second most prevalent anemia globally particularly in conditions of prolonged immune activation including hemodialysis (HD). While the role of pro-inflammatory cytokines in disrupting iron homeostasis and erythropoiesis is well-established, the regulatory mechanisms involving microRNAs (miRNAs) remain incompletely elucidated. The current study investigates the intricate relationships between cytokines and miRNAs in the pathogenesis of AI among HD patients. The study comprised 30 HD patients with AI and 30 healthy controls. Expression profile of inflammatory cytokines (IL-6, TNF-α) and inflammation-associated miRNAs (miR-34, miR-130, miR-16b) were analyzed using quantitative real-time PCR. Serum C-reactive protein (CRP) and iron metabolism markers (serum iron, ferritin, transferrin saturation and total iron binding capacity) were analyzed. Correlation analyses and pathway enrichment studies were performed to identify cytokine-miRNA regulatory networks. HD with AI exhibited significant overexpression of IL-6, TNF-α and miR-34 ( p  < 0.001), while miR-130 and miR-16b were significantly downregulated ( P  < 0.001) compared to control group. MiR-34 was positively correlated with IL-6 ( r  = 0.96, p  = 0.001) and TNF-α ( r  = 0.98, p =  0.001), while it showed significant inverse correlation with miR-130 and miR-16b ( p =  0.001 for both). Furthermore, strong positive associations were observed between lower levels of transferrin saturation and decreased expression of IL-6, TNF-α and miR-16b ( p =  0.01, 0.009, 0.001 respectively). The markedly increased ferritin levels (> 600 mg/mL) showed direct positive relationship with elevated expression of IL-6 and TNF-α in HD with AI. The present findings are exploratory and hypothesis-generating, suggesting possible relationship between miRNA dysregulation and the development of AI in HD patients, and provide the rationale for external validation in larger, independent HD cohorts. The interaction between miRNA expression and cytokine signaling may provide novel insights into the mechanism that could perpetuate AI in HD unravelling potential therapeutic targets that could mitigate the inflammatory response ultimately improving patient outcomes.